Myocardial late gadolinium enhancement using delayed 3D IR-FLASH in the pediatric population: feasibility and diagnostic performance compared to single-shot PSIR-bSSFP

Background This study compares three-dimensional (3D) high-resolution (HR) late gadolinium enhancement (LGE; 3D HR-LGE) imaging using a respiratory navigated, electrocardiographically-gated inversion recovery gradient echo sequence with conventional LGE imaging using a single-shot phase-sensitive inversion recovery (PSIR) balanced steady-state free precession (bSSFP; PSIR-bSSFP) sequence for routine clinical use in the pediatric population. Methods Pediatric patients (0–18 years) who underwent clinical cardiovascular magnetic resonance (CMR) with both 3D HR-LGE and single-shot PSIR-bSSFP LGE between January 2018 and June 2020 were included. Image quality (0–4) and detection of LGE in the left ventricle (LV) (per 17 segments), in the right ventricle (RV) (per 3 segments), as endocardial fibroelastosis (EFE), at the hinge points, and at the papillary muscles was analyzed by two blinded readers for each sequence. Ratios of the mean signal intensity of LGE to normal myocardium (LGE:Myo) and to LV blood pool (LGE:Blood) were recorded. Data is presented as median (1st–3rd quartiles). Wilcoxon signed rank test and chi-square analyses were used as appropriate. Inter-rater agreement was analyzed using weighted κ-statistics. Results 102 patients were included with median age at CMR of 8 (1–13) years-old and 44% of exams performed under general anesthesia. LGE was detected in 55% of cases. 3D HR LGE compared to single-shot PSIR-bSSFP had longer scan time [4:30 (3:35–5:34) vs 1:11 (0:47–1:32) minutes, p < 0.001], higher image quality ratings [3 (3–4) vs 2 (2–3), p < 0.001], higher LGE:Myo [23.7 (16.9–31.2) vs 5.0 (2.9–9.0), p < 0.001], detected more segments of LGE in both the LV [4 (2–8) vs 3 (1–7), p = 0.045] and RV [1 (1–1) vs 1 (0–1), p < 0.001], and also detected more cases of LGE with 13/56 (23%) of patients with LGE only detectable by 3D HR LGE (p < 0.001). 3D HR LGE specifically detected a greater proportion of RV LGE (27/27 vs 17/27, p < 0.001), EFE (11/11 vs 5/11, p = 0.004), and papillary muscle LGE (14/15 vs 4/15, p < 0.001). Inter-rater agreement for the recorded variables ranged from 0.42 to 1.00. Conclusions 3D HR LGE achieves greater image quality and detects more LGE than conventional single-shot PSIR-bSSFP LGE imaging, and should be considered an alternative to conventional LGE sequences for routine clinical use in the pediatric population. Supplementary Information The online version contains supplementary material available at 10.1186/s12968-023-00917-0.


Background
Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) evaluation of myocardial injury and fibrosis provides essential diagnostic and prognostic information in a variety of congenital and pediatric heart conditions [1][2][3][4]. One of the conventional methods of performing LGE imaging is by using a twodimensional single-shot phase-sensitive inversion recovery (PSIR) balanced steady-state free precession (bSSFP; PSIR-bSSFP) sequence [1]. Recently, a three-dimensional (3D) high-resolution (HR) LGE (3D HR-LGE) option using a respiratory navigated, electrocardiographically (ECG)-gated inversion recovery gradient echo sequence has been described [5][6][7]. This sequence, that is widely used for contrast-enhanced CMR angiography [8,9], has also been investigated for routine clinical use for LGE imaging in adult patients for selected conditions, such as ischemic cardiomyopathy, atrial and ventricular arrhythmias, and tetralogy of Fallot [7].
Advantages of 3D HR-LGE include higher spatial resolution, increased signal to noise, better fat saturation, and ability to perform multiplanar reconstructions. Disadvantages include a long scan time and potential for compromised quality due to inconsistent breathing, motion, significant heart rate variation, arrhythmia, or inappropriate inversion time [7]. The performance of 3D HR-LGE in the pediatric population has not yet been investigated.
The purpose of this study was to evaluate the use of a 3D HR-LGE sequence compared to a conventional single-shot PSIR-bSSFP LGE sequence for detection of LGE in routine pediatric clinical CMR.

Study population
This single institution retrospective study received institutional Research Ethics Board approval with waiver of informed consent. Patients between 0 and 18 years of age that underwent a clinical CMR that included LGE imaging performed between January 2018 and June 2020 were included. CMRs that did not have both 3D HR-LGE and single-shot PSIR-bSSFP LGE were excluded. This was related to variable adoption of 3D HR-LGE early in the inclusion period along with standardization of our clinical practice by using conventional single-shot PSIR-bSSFP LGE exclusively as opposed to occasional alternative use of conventional segmented PSIR-FLASH LGE. Non-diagnostic exams related to technical factors were also excluded, which mostly were related to variable attempts at optimization of technique parameters early in the adoption period. Note that exams with excessive patient motion artifact were not excluded.

CMR acquisition
Studies were performed on a 1.5 T CMR system (Avanto Fit, Siemens, Healthineers, Erlangen, Germany). Conventional LGE was performed using a two-dimensional single-shot PSIR-bSSFP sequence acquired in axial and short-axis planes 10 min following intravenous injection of 0.2 mmol/kg of gadobutrol (Gadovist; Bayer Healthcare, Berlin, Germany). 3D HR-LGE was performed using a 3D ECG-gated, respiratory-navigated inversion recovery-prepared (IR) fast low angle shot (FLASH) pulse sequence with fat saturation acquired in coronal plane, and obtained 15-20 min following intravenous administration of gadolinium-based contrast agent. Respiratory navigation was performed using pencil-beam navigation. As exact nulling of myocardium is not necessary for this sequence, an empiric inversion time of 220 ms was used with quiescent interval chosen in systole. However, when the Look-Locker acquired before conventional LGE gave a myocardial nulling inversion time ≥ 300 ms, an empiric inversion time of 280 ms was used for the 3D HR-LGE sequence with quiescent interval in diastole. Other specific sequence parameters are shown in Table 1. Isotropic axial and ventricular short axis planes in the native resolution were reconstructed for the 3D HR-LGE sequence for purposes of analysis.

CMR analysis
Each sequence was analyzed by two independent, blinded readers (A.S and J.A.). Presence or absence of LGE per myocardial segment was recorded for each sequence. The left ventricle (LV) was divided into 17 myocardial segments according to standardized American Heart Association LV segmentation [10]. The right ventricle (RV) was divided into three segments: inlet, apical and outlet. In addition, presence of endocardial fibroelastosis (EFE), subendocardial LGE, mid-myocardial LGE, subepicardial LGE, or LGE at the ventricular hinge points and papillary muscles were also recorded. For cases where there was disagreement between presence and absence of LGE, consensus was reached for final analysis via a third reader (C.Z.L.). Image quality of each sequence was rated on a fourpoint ordinal scale: (1) poor with no clear distinction of myocardial margins; (2) fair with blurred myocardial edges; (3) good with clear myocardial margins; (4) very good with sharp myocardial margins ( Fig. 1).
When myocardial LGE was detected on both sequences, the mean signal intensity of LGE, normal myocardium, and LV blood pool were measured using manually drawn regions of interest. LGE to myocardium (LGE:Myo) and LGE to LV blood pool (LGE:Blood) signal intensity ratios were calculated and compared.

Statistical analysis
Continuous variables are summarized as median (1st-3rd quartiles) and categorical variables are summarized as frequency (percentage). κ-statistics were used for inter-rater agreement of LGE detection and image quality ratings between the two sequences. Wilcoxon signed rank test and chi-square analyses were used to compare conventional LGE and 3D HR LGE sequences. All statistical tests were two-sided and considered statistically significant if p < 0.05. Analyses were performed using SPSS for Windows (version 28.0.0.0, Statistical Package for the Social Sciences, International Business Machines, Inc., Armonk, New York, USA).

Patient selection and demographics
One-hundred and sixty-six patients underwent clinical CMR that included LGE imaging during the study period. Thirty-eight patients were excluded due to the lack of concomitantly performed 3D HR-LGE and conventional single-shot PSIR-bSSFP LGE sequences. One patient was excluded due to extra-cardiac artifact obscuring the heart. Twenty-six (20%) of the remaining patients were   Table 2.

p-value
LGE in any location

Inter-rater agreement
Inter-rater agreement via weighted κ-statistics was 0.86 [95% CI 0.79-0.93] for 3D HR LGE image quality ratings, 0.60 [95% CI 0.46-0.74] for single-shot PSIR-bSSFP LGE image quality ratings, and ranged from 0.42 to 1.00 for detection of LGE depending on myocardial location and sequence. Inter-rater agreement was not clearly different between the two techniques, with overlapping 95% confidence intervals. This data is summarized in Additional file 1: Table S1.

Discussion
In this study, a 3D HR-LGE sequence was compared with conventional single-shot PSIR-bSSFP LGE imaging as a clinical routine in the pediatric population. The key findings of this work are that 3D HR-LGE is feasible for routine use in pediatric clinical CMR, and compared to single-shot PSIR-bSSFP LGE, achieves greater image quality and detects more LGE, particularly for the RV, EFE, and papillary muscles. Some of the disadvantages of a 3D HR-LGE sequence relate to the long scan time that may result in patient motion and suboptimal image quality. In this cohort, 3D HR-LGE was performed with a median scan time of 4.5 min, which is shorter than reported in adults with an average of 10 min [7]. This may be related to faster heart rates, faster respiratory rates, and smaller size of children. Conversely, single-shot PSIR-bSSFP sequences suffer from low signal in small children with fast heart rates. 3D HR-LGE may thus be well suited for the pediatric population, particularly when the study is performed under general anesthesia or sedation where respirations are better controlled. Indeed, in this study we confirm that 3D HR-LGE shows greater image quality and a four to fivefold higher LGE:myo signal intensity compared with conventional LGE.
This translated to superior diagnostic performance with 3D HR-LGE detecting both more patients with LGE, and greater extent of LGE when present. In fact, in 23% of patients that had LGE, the LGE was not detectable by single-shot PSIR-bSSFP. The performance of 3D HR-LGE was particularly superior for LGE of small or thin structures, comparable to the use of 3D HR-LGE for the atrium in adults [11]. In our population, this improved performance was most evident for RV LGE, EFE, and papillary muscle LGE, where single-shot PSIR-bSSFP missed up to 37% of RV LGE, 55% of EFE, and 38% of papillary muscle LGE. Some of the superior performance for RV LGE may be related to the fact 3D HR-LGE was primarily performed in systole whereas single-shot PSIR-bSSFP was performed in diastole, however, the improved spatial resolution and signal of the 3D HR-LGE sequence was also likely beneficial. The fact that 3D HR-LGE was superior to PSIR-bSSFP for detection of LGE in all myocardial layers, along with the similar LGE:blood signal intensity, suggests that improved contrast between subendocardial LGE and blood pool was not necessarily the primary driver of superior performance in this study. Therefore, this technique may be adjunctive to proposed dark-blood or gray-blood LGE strategies that aim to optimize LGE:blood contrast [12]. Importantly, 3D HR-LGE did not miss any clinically significant LGE in our study (only two cases of hinge point LGE that was related to patient motion on the 3D HR-LGE sequence), and in fact, helped to show apparent LGE on single-shot PSIR-bSSFP sequences were false positives in 2 cases. Our data therefore supports using 3D HR-LGE as a clinical standard in the pediatric population.
Of practical considerations for implementation, this sequence is widely available and can be repeated for both angiography and LGE imaging in the same exam. It does not preclude perfusion imaging, conventional LGE, or T1/ECV mapping. At our institution we no longer perform conventional LGE sequences for non-cardiomyopathy patients.

Limitations
Our study is limited by its retrospective design using clinical cases that did not allow for strict control of technical parameters. The true failure rate of the 3D HR-LGE sequence could not be determined as we included examinations performed during our testing and adoption Fig. 6 Comparison of 3D HR-LGE and conventional single-shot PSIR-bSSFP LGE sequences performed free-breathing under general anaesthesia in a 4-year-old patient with hypoplastic left heart syndrome, showing circumferential LV endocardial fibroelastosis (solid arrowheads) and focal LGE of an RV papillary muscle (empty arrowheads). Both endocardial fibroelastosis and papillary muscle LGE are not clearly identifiable on the single-shot PSIR-bSSFP sequence